RMD Open最新文献

Objectives: To explore characteristics and treatment of patients with rheumatoid arthritis (RA) with invasive fungal infections (IFIs) and to describe infection details and outcome.

Methods: IFIs reported to the German RABBIT (Rheumatoid Arthritis: Observation of Biologic Therapy) register between May 2001 and December 2023 were analysed using a two-stage approach. First, a detailed case description, including a comparison of cases by infection outcome, was conducted using routine register data and hospital discharge letters. Second, a multivariable time-dependent Cox regression model was fitted to analyse associations with IFI development using routine register data only.

Results: Among 22 535 patients with RA, 69 IFIs occurred (incidence rate: 0.65/1000 patient-years), with a case fatality of 35% (n=24). Causative pathogens were Pneumocystis jirovecii (35%), Candida spp (33%) and Aspergillus spp (13%).Patients with IFIs were on average 65.4 years old; 54% were female, 80% ever-smokers, 84% glucocorticoid (GC) users and 91% had any infection-risk associated comorbidity at hospitalisation. IFI development was associated with older age (HR 1.36 per 10 years (95% CI 1.05 to 1.76)), male sex (HR 1.92 (95% CI 1.14 to 3.21)), ever-smoking (HR 2.43 (95% CI 1.35 to 4.37)), cardiovascular disease (HR 3.03 (95% CI 1.80 to 5.10)), chronic lung disease (HR 2.09 (95% CI 1.21 to 3.61)), other autoimmune disease (HR 2.11 (95% CI 1.10 to 4.07)), and the use of GCs (HR 1.17 (95% CI 1.11 to 1.22)).

Conclusion: In patients with RA, IFIs are rare but life-threatening. They occur particularly in patients who are predisposed to infection due to relevant comorbidities, a history of smoking or both. Except for GC use, the overall impact of targeted RA treatment on the risk of IFI appears to be less relevant than that of multimorbidity.

Objective: To assess the long-term safety and efficacy of upadacitinib over 5 years in Japanese patients with moderate-to-severe active rheumatoid arthritis and an inadequate response to stable doses of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs-IR).

Methods: Japanese patients received upadacitinib 7.5, 15 or 30 mg once per day or placebo for 12 weeks in a double-blind, randomised manner. Patients who completed the placebo-controlled phase entered a long-term extension phase during which they continued the same upadacitinib dose or were switched from placebo to upadacitinib 7.5, 15 or 30 mg once per day. Blinding was maintained until dose switching from upadacitinib 30 mg to 15 mg, prior to the regulatory approval of 15 mg; the earliest switch occurred at week 132. Safety and efficacy were evaluated through week 260.

Results: In total, 121/187 (64.7%) patients who entered the long-term extension phase completed the study. The types and frequency of adverse events were comparable with those reported at week 84 and in other studies of upadacitinib. The incidences of any adverse events, serious adverse events, infection and serious infection were numerically higher on upadacitinib 15 and 30 mg than on 7.5 mg. Clinical outcomes were improved and maintained over 260 weeks; Clinical Disease Activity Index clinical remission rates after 5 years were 40.8%, 26.5% and 28.0% on upadacitinib 7.5, 15 and 30 mg, respectively (non-responder imputation).

Conclusions: Upadacitinib showed sustained efficacy with no new safety signals identified through 5 years of treatment and is a long-term treatment option for Japanese patients with rheumatoid arthritis and csDMARDs-IR.

Objective: To determine the prevalence of poor health-related quality of life (HRQoL) in patients with systemic lupus erythematosus (SLE) in Lupus Low Disease Activity State (LLDAS) or Definitions of Remission in SLE (DORIS) remission and sustained LLDAS or sustained DORIS remission, after a 52-week therapeutic intervention.

Methods: We analysed data from four phase III trials of belimumab in SLE (BLISS-52, BLISS-76, BLISS-SC, EMBRACE; n=2406). Sustained LLDAS/remission was defined as persistent LLDAS/remission for at least two visits, maintained through week 52. Poor HRQoL was defined as Short Form-36 (SF-36) physical/mental component summary (PCS/MCS) and domain scores ≤the normative fifth percentile, Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) scores <30 and responses of 'some/moderate problems' or 'extreme/major problems' in any of the five dimensions of the three-level version of EuroQol 5-Dimension (EQ-5D) health questionnaire.

Results: At week 52, among patients in LLDAS, remission, sustained LLDAS and sustained remission, 15.7%, 13.6%, 14.3% and 9.0% reported poor SF-36 PCS, and 12.5%, 11.4%, 12.9% and 14.0% reported poor SF-36 MCS scores, respectively. The highest frequencies were reported in the physical functioning domain (24.0%-26.3%), while 18.5%-26.2% reported FACIT-F scores 30. Among EQ-5D dimensions, pain/discomfort yielded the greatest frequencies of poor HRQoL experience (27.9%-28.7%). While significant improvements were observed among patients achieving the treatment goals in all HRQoL outcomes over the 52-week study period, PCS scores remained below population norms.

Conclusions: Despite LLDAS or DORIS remission, notable proportions of SLE patients report poor HRQoL, indicating that current therapeutic goal definitions do not fully capture patients' perspectives of health.

Objective: To describe the joint manifestations associated with clonal haematopoiesis and to compare patients with and without VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome.

Methods: Patients screened for UBA1 mutations between December 2019 and January 2023 in 7 Normandie (France) hospitals were recruited retrospectively.

Results: Thirty patients with a haematological disorder associated with dysimmune manifestations were included: 17 (57%) without UBA1 mutations (non-VEXAS) and 13 (43%) with UBA1 mutations (VEXAS). Thirteen (77%) non-VEXAS patients had joint involvement (arthralgia/arthritis), compared with 4 (31%) VEXAS patients (p value: 0.016). Unsupervised clustering using hierarchical clustering identified two clusters. Cluster 1 (14 patients) had more joint involvement (93% vs 25%, p value: 0.001), less UBA1 mutation (14% vs 69%, p value: 0.008), pulmonary involvement (7% vs 50%, p value: 0.017), chondritis (0% vs 50%, p value: 0.003) and unprovoked venous thrombosis (7% vs 43%, p value: 0.039) than cluster 2 (16 patients). Cluster 1 had more ASXL1 mutations (21% vs 0%).

Conclusion: Joint involvement was more frequent in patients with clonal haematopoiesis and dysimmune manifestations unrelated to VEXAS syndrome.

Objectives: To compare the spondyloarthritis (SpA) specific universal health utility estimation from the ASAS health index (U-ASAS-HI) with the generic EuroQol-5D-3L (EQ-5D-3L) utility among SpA subtypes and to understand the contribution of health-, personal- and country-level factors to the U-ASAS-HI.

Methods: Ancillary analysis of the ASAS-PERipheral involvement in SpondyloArthritis (PerSpA) study including patients who completed both ASAS-HI and EQ-5D-3L. Correlations between U-ASAS-HI and EQ-5D-3L were tested overall and by subtype (axial SpA, peripheral SpA and psoriatic arthritis (PsA)). Health and contextual determinants of U-ASAS-HI were evaluated using multivariable linear mixed-effects models with country as level.

Results: 4158 patients were included, mean age 44 (SD:13) and 61% male. Mean U-ASAS-HI was 0.44 (SD:0.30) and mean EQ-5D-3L was 0.71 (SD:0.21), with numerically minor differences between subtypes. Correlations between U-ASAS-HI and EQ-5D-3L were consistently strong between subgroups (range 0.74-0.76). Linear mixed-effects modelling showed health outcomes, including disease activity (axial spondyloarthritis disease activity score; β=-0.030, 95% CI -0.038 to -0.021), physical function (bath ankylosing spondylitis functional index; β=-0.044, 95% CI -0.048 to -0.041), anxiety/depression (EQ-5D-3L q5; β=-0.147, 95% CI -0.160 to -0.134) and fibromyalgia (fibromyalgia rapid screening tool; β=-0.068, 95% CI -0.083 to -0.053) were strong predictors of lower U-ASAS-HI. Additionally, female gender, PsA subtype, axial involvement, fatigue and having no employment were associated with lower U-ASAS-HI while older age and university education were associated with higher U-ASAS-HI. The random-effects model indicated an intraclass correlation coefficient of 6% in total variance attributable to differences between countries.

Conclusion: The universal U-ASAS-HI captures the broad range of aspects relevant to valuing SpA health states across SpA subtypes. The lower absolute values of U-ASAS-HI reflect the wider disutility associated with SpA.

Objective: Interstitial lung disease (ILD) represents the most common and severe organ manifestation observed in patients diagnosed with connective tissue diseases (CTDs). The aim of this retrospective cross-sectional study was to identify clinical risk factors such as pulmonary symptoms, age, gender, laboratory and pulmonary function test (PFT) parameters associated with the extent of ILD as measured by artificial intelligence-based quantification of pulmonary high-resolution computed tomography (AIqpHRCT).

Methods: We included patients with a CTD-ILD diagnosis; all underwent PFT and HRCT, and pulmonary symptoms and signs of inflammation were also documented. AIpqHRCT was used to quantify lung volumetry and ILD features including ground glass opacities (GGO), reticulations, high-attenuation lung volume (HAV), emphysema and overall extent of ILD. Finally, 76 CTD-ILD patients were eligible for regression analysis, in order to evaluate the influence of clinical parameters on ILD extent.

Results: The reduction of diffusing capacity of the lung for carbon monoxide (DLCO), total lung capacity (TLC) and elevated inflammation parameter was significantly associated with the extent of GGO, reticulations, HAV and overall extent of ILD. Pulmonary symptoms, age and forced vital capacity were not associated with the extent of ILD quantified by AIqpHRCT.

Conclusion: The study presented that DLCO and TLC were predictive for the CTD-ILD severity. Consequently, our findings suggest the performance of PFT, including DLCO for all patients with CTD. In the case of reduced DLCO and TLC, further diagnostics, including HRCT, are necessary.

Objective: To investigate the association between peripheral disease activity and pre-eclampsia, gestational hypertension, preterm birth and fetal growth in women with psoriatic arthritis (PsA).

Methods: Data from a Norwegian nationwide register (RevNatus) were linked with data from the Medical Birth Registry of Norway (MBRN). Cases were singleton births in women with PsA with available disease activity assessment (n=109) included in RevNatus 2010 to 2019. Singleton births registered in MBRN during the same decade served as population controls (n=575 798). Disease activity was assessed by Disease Activity Score based on 28 joints using C reactive protein (DAS28-CRP) in 2nd and 3rd trimester. Active PsA was defined as DAS28-CRP≥2.6 (n=34) and inactive PsA as DAS28-CRP<2.6 (n=75).

Results: Pre-eclampsia was most frequent in women with active PsA (3/34, 8.8%), with a risk difference of 6.1% (95% CI 0.3 to 20.3, p=0.036) compared with population controls (2.6%). Gestational hypertension occurred in 2/34 (5.9%) of women with active PsA, with a risk difference of 4.2% (95% CI 0.0 to 17.4, p=0.065) compared with population controls (1.7%). Pre-eclampsia and gestational hypertension occurred in similar proportions in women with inactive PsA (1.3%, p=0.59 and 2.7%, p=0.24, respectively) and population controls. The occurrence of preterm birth and abnormal fetal growth was comparable in cases and population controls.

Conclusion: Hypertensive disorders of pregnancy occurred more often in women with active, but not inactive PsA. We found no increased risk for preterm birth or abnormal fetal growth in women with PsA.

Objective: To summarise the measurement properties of instruments used to assess fatigue in people with rheumatic and musculoskeletal diseases (RMDs).

Methods: A systematic review (SR) of measurement properties was conducted in children, adolescents/young adults and adults with RMDs, following Joanna Briggs Institute and COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) guidelines. Searches were performed in Medline, Embase, CINAHL and Cochrane Library. Risk of bias assessment, data extraction and synthesis were conducted independently by two reviewers. Instruments were assessed according to Outcome Measures in Rheumatology (OMERACT) criteria.

Results: Out of 16 657 records, 109 articles underwent full-text review, and 60 met inclusion criteria. These studies evaluated the psychometric properties of 27 instruments. Most studies focused on construct validity (54/60, 90%) and intermethod reliability (45/60, 75%), with an overall low risk of bias. In contrast, test-retest reliability (13/60, 21.7%) and responsiveness (14/60, 23.3%) were less frequently assessed, but also with an overall low risk of bias. Evidence regarding clinical trial discrimination and thresholds of meaningful change was limited or absent, indicating the need for further research in these domains. Only five instruments-the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue, the 36-Item Short Form Survey Instrument (SF-36) Vitality, the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire (BRAF-MDQ), the BRAF Numerical Rating Scales (BRAF-NRS) and the Fatigue Severity Scale (FSS)-were rated as valid, reliable and low risk of bias, fulfilling OMERACT endorsement criteria.

Conclusions: This SR comprehensively supports the use of several well-validated instruments to assess fatigue, particularly FACIT-Fatigue, SF-36 Vitality, BRAF-MDQ, BRAF-NRS and FSS, in both clinical and research settings.

Prospero registration number: CRD42024507112.

Background: Disappointing outcomes in Sjögren's disease (SjD) trials underscore the need for reliable, sensitive endpoints. Histological assessment holds promise, but a minimally invasive, repeatable method for salivary gland tissue sampling is lacking.

Objectives: To evaluate the feasibility, safety and tissue adequacy of ultrasound-guided core needle biopsy (US-guided CNB) of the parotid gland and explore its role for facilitating histology-driven stratification and precision medicine.

Methods: In the Belgian Sjögren's Syndrome Transition Trial, 66 patients (64 without gland swelling) underwent US-guided CNB. US was evaluated using OMERACT (Outcome Measures in Rheumatology Clinical Trials). and Hocevar scoring. Histopathology included assessment of focus score, B cell predominance (CD20>CD3), follicular dendritic cell networks (CD21), plasma cells (CD138), lymphoepithelial lesions (CK7/CK14) and FcRL4+ B cells. Pain was assessed using a visual analogue scale (VAS) from 0 to 10. Findings were matched with clinical data.

Results: Mean VAS pain scores were 2.7 (SD=2.77) during biopsy and 1.9 (SD=2.33) in the 3 days before the follow-up call at day 14. No major complications occurred, and 82% of patients were willing to repeat the procedure. Adequate tissue was retrieved in 62/66 cases. Patients showed histological heterogeneity and were, as proof of concept, stratified into mild, moderate and severe histological involvement. Histological severity correlated with ultrasound scores (p<0.01) and not with traditional outcome measures (European Alliance of Associations for Rheumatology Sjögren's Syndrome Patient-Reported Index dryness and European Alliance of Associations for Rheumatology Sjögren's Syndrome Disease Activity Index).

Conclusion: US-guided CNB is safe, well-tolerated and yields adequate tissue. Beyond diagnostics, it might facilitate histology-driven patient stratification and advance precision medicine for SjD.

Background: Mixed connective tissue disease (MCTD) has long been debated as an early nonspecific phase/symptom of differentiated connective tissue diseases (dCTD), similarly to interstitial pneumonia with autoimmune features (IPAF) and very early diagnosis of systemic sclerosis (SSc) (VEDOSS).

Objective: We aimed to evaluate the predictive value of IPAF, VEDOSS and dCTD classification criteria variables in MCTD patients.

Methods: We conducted an observational study within the French MCTD cohort. IPAF, VEDOSS and current dCTD classification criteria were used to classify patients.

Results: Three hundred and twenty-four MCTD patients were included and followed for 8 (3.3-13) years. Among them, 111 (34.3%) progressed into a dCTD, that is, 50 (15.4%) SSc, 40 (12.3%) systemic lupus erythematosus (SLE) and 11 (3.4%) Sjögren's disease. At diagnosis, 38 (11.7%) patients fulfilled IPAF criteria, among which 15 (39.5%) progressed into a dCTD (vs 75 (26.2%) in patients who did not fulfil IPAF criteria; p=0.09). At diagnosis, 293 (90.4%) patients fulfilled VEDOSS criteria but did not progress significantly more frequently to SSc than MCTD patients without VEDOSS criteria (46 (15.7%) vs 4 (12.9%); p=0.8). At baseline, SSc classification criteria did not predict evolution toward SSc, whereas antiphospholipid antibodies and low C3 and/or C4 were predictive of an evolution toward SLE (p=0.01 and p=0.04, respectively).

Conclusion: At MCTD diagnosis, fulfilment of IPAF and/or VEDOSS criteria was not predictive of evolution toward SSc, whereas antiphospholipid antibodies and low C3 and/or C4 were predictive of an evolution toward SLE. This suggests that MCTD patients should be excluded from IPAF and VEDOSS.